OR28-4 Spontaneous Autoimmune Diabetes in Humanized Mice Carrying Human Type 1 Diabetes Susceptibility
Journal of the Endocrine Society(2019)
摘要
An animal model of type 1 diabetes (T1D), in which human beta cell autoantigen(s) are presented to effector cells in the context of human Major Histocompatibility Complex (MHC) diabetes-susceptibility genes, would be highly desirable for studies of molecular mechanisms of disease and development of antigen-specific immune-therapies applicable to man. It would be especially advantageous to develop an animal model of human T1D that also exhibits the chronic complications of diabetes. Our new spontaneous mouse model of T1D wherein mouse MHC-II was replaced by human DQ8 in all antigen-presenting cells (APCs), and pancreatic Beta-cells were made to express human GAD65 autoantigen resembles most human characteristics of the disease. Our humanized transgenics have a genetic background providing for compromised Beta-cell neogenesis and/or regeneration. Immune cells attack Beta-cells, which in turn leads to a chronically progressive disease characterized by the development of anti-GAD65 antibodies. Flow cytometric analysis of pancreas (PN) and peri-pancreatic lymph nodes (PLN) revealed that CD4 and CD8 T cells build up in the PLN while mostly CD8 infiltrate intra-islet locations, which first causes glucose intolerance, and later on diabetes. Animals spontaneously show hyperglycemia of >250 mg/dl at approximately eight weeks of age. Without intervention, animals develop the classic complications observed in human diabetes (i.e., retinopathy, nephropathy, and neuropathy). To date, all complications of diabetes have been observed in our model (1). Our humanized transgenics develop diabetic retinopathy. Diabetic mice develop a significant increase of acellular capillaries in the retina as compared to non-diabetic controls as early as 6 months. Ocular tomography revealed that total retinal thickening was reduced in diabetic mice. Fundoscopic retinal images also revealed vascular leakage only in diabetic mice. Six-month-old diabetic mice also show advanced features of diabetic nephropathy like focal segmental/global glomerular sclerosis and focal tubular atrophy. Basal glomerular membrane doubles in size at three months as shown by electron microscopy as compared to non-diabetic controls. Moreover, our humanized mice also show diabetic neuropathy. Optic nerves of 6-month-old diabetic mice show an increase in the refractory period of the second compound action potential (CAP) as compared to non-diabetic mice (p < 0.05). This increase in the refractory period of CAP in the diabetic optic nerves is consistent with the reduced conduction velocity over non-diabetic controls. Conclusively, our humanized mice model is the closest one to human diabetes and is not just suitable for therapies to halt diabetes and its development but also to address the physiopathology and treatment of diabetes complications. 1) U.S. Provisional Patent #62/713,827 Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.
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关键词
Type 1 Diabetes,Diabetes,Continuous Glucose Monitoring
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